The present invention generally relates to a method for delivering therapeutic agents into the brain, and more specifically to such a method in which the therapeutic agents are delivered across the blood brain barrier.
In treating diseases of the brain and central nervous system, it would be advantageous to have a practical method for delivery of a drug across the blood brain barrier (BBB). The BBB is a capillary barrier comprising a continuous layer of tightly bound endothelial cells. These cells permit a low degree of transendothelial transport, and exclude molecules in the blood from entering the brain on the basis of molecular weight and lipid solubility, as described in Neuwelt, E. A., "Is There A Therapeutic Role For Blood-Brain Barrier Disruption" Ann. Int. Med. 93: 137-139, 1980. For example, the blood brain barrier normally excludes molecules with a molecular weight greater than 180 daltons. In addition, the lipid solubility of molecules is a major controlling factor in BBB passage.
Considerable research has been conducted relating to the BBB and its permeability. Articles involving permeability of the BBB include:
1. "Chemotherapy of brain metastases: Current status" Greig, N. H., Cancer Treatment Reviews, 11: 157-186 (1984). PA1 2. "Cerebrovascular permeability and delivery of gentamicin to normal brain and experimental brain abscess in rats", Neuwelt, E. A., et al, Journal of Neurosurgery, 61: 430-439 (1984). PA1 3. "Blood-Brain Barrier: Phenomenon of Increasing Importance to the Imaging Clinician", Sage, M. R., American Journal of Roentgenology, 138: 887-898 (1982). PA1 4. "Opening the Blood-Brain and Blood-Tumor Barriers in Experimental Rat Brain Tumors: The Effect of Intracarotid Hyperosmolar Mannitol on Capillary Permeability and Blood Flow", Hiesinger, E. M. et al, Annals of Neurology, 19: 50-59 (1986).
The foregoing articles discuss the permeability characteristics of the BBB in terms of lipid solubility, ionization fraction, protein binding and/or the molecular weight of foreign molecules. As specifically described by Sage, the function of the BBB is to maintain the homeostasis of the neuronal environment. The continuity produced by the tight junctions between individual cells of the BBB enables the cerebrocapillary endothelium to act like a plasma membrane. Small molecules (m.w. &lt;200 daltons) having a high degree of lipid solubility and low ionization at physiological pH are freely passed through the BBB. In addition, the BBB allows water to move in either direction in order to maintain equal osmotic concentrations of solutes in the extracellular cerebral fluid.
However, recent research has shown that the BBB may become increasingly permeable during the development or onset of brain tumors, vascular lesions, or abscesses. As discussed by Sage, the cerebrocapillary endothelium has a close investment by a glial sheath. Destruction of the glial sheath by mitotic activity may make the capillaries therein more permeable. Tumors appear to stimulate the proliferation of abnormal capillaries by releasing specific angiogenic factors in the brain.
The unique biological aspect of the BBB is an important focus in treating central nervous system disorders. While the interendothelial junctions between the cells of the BBB are normally designed to keep potentially noxious substances away from the brain, this condition changes during the formation of brain abscesses, inflammation, and/or tumors, as described above. For example, tests have shown that experimental allergic encephalomyelitis (EAE) may cause an immune reaction which increases the permeability of the BBB. Alvoode, E. C. et al, "Experimental Allergic Encephalomyelitis: A Useful Model For Multiple Sclerosis", Prog. Clin. Biol. Res., Vol. 146, Alan, R., Liss Co., New York, 1984. One explanation for the increased permeability of the BBB at the onset of EAE involves the capability of endothelial cells of the cerebrovasculature system to act as antigen presenting cells (APCs), thus attracting T-cells and aiding their penetration across the BBB. Accordingly, it has been found that brain endothelial cells are capable of expressing histocompatibility antigens on their surfaces.
Another possible explanation for the increase in the permeability of the BBB during the onset of lesions involves the ability of the brain under these circumstances to generate vasoactive substances, as described in Black, K. L., "Leukotrienes Increase Blood-Brain Barrier Permeability Following Intraparenchymal Injections In Rats." Ann. Neurol., 18: 349-351, 1985. Brain lipids are rich in arachidonic acid which may be released by trauma to the brain tissue, e.g., by neoplastic invasion or ischemia. Black has shown experimentally that arachidonic acid and leukotrienes can increase BBB permeability when injected directly into the rat brain. Leukotriene content of the brain tissue correlates significantly with the amount of edema surrounding various CNS neoplasms, and it is conceivable that leukotrienes released from the damaged brain contribute to BBB disruption and vasogenic edema in CNS neoplasia.
Likewise, inflammation of brain tissue in immune-mediated CNS disease might possibly cause release of arachidonic acid and leukotrienes which would increase the permeability of the BBB. A further discussion of increased BBB permeability with reference to nervous system disorders, including infections, inflammatory conditions, neoplasms, and ischemia is presented in Fishman, R. A., Cerebrospinal Fluid in Diseases of the Nervous System, W. B. Saunders Co., Philadelphia, London, Toronto, 1980; Tourtelotte, W. "On Cerebrospinal IgG Quotients In Multiple Sclerosis and Other Diseases. A Review And A New Formula To Estimate The Amount Of IgG Synthesized Per Day By the Central Nervous System", J. Neurol. Sci., 10: 279-304, 1970.
As described herein, the increased permeability of the BBB caused by brain lesions can be used in the administration of drugs designed to treat these problems. However, care must be taken to insure that the use of drugs under these conditions does not result in physiological toxicity due to drug overdosage. This frequently occurs since large doses of drugs are often required to treat lesions such as abscesses or tumors of the brain, especially if multiple abscesses or tumors are involved.
One method for treating brain tumors which includes a control mechanism to prevent drug overdosage is disclosed in the above-cited Cancer Treatment Reviews article. Page 164 of the article discusses a technique involving the administration of high doses of methotrexate followed within 24-36 hours by an additional technique called "leucovorin rescue". Methotrexate chemically prevents tumor proliferation by binding almost irreversably to the enzyme dihydrofolate reductase which prevents the formation of the coenzyme tetrahydrofolate, an essential material for DNA synthesis. In order to control an overdose of methotrexate, leucovorin is added which supplies the tissues with additional tetrahydrofolate, resulting in diminished patient toxicity without eliminating the anti-tumor effect of methotrexate. However, use of this method is not possible for most drugs.
Thus, a need currently exists for a method designed to administer therapeutic agents across the BBB for the treatment of brain lesions, while avoiding problems associated with systemic overdosage. The present invention represents a method for accomplishing these goals.